Trandolapril (1) [CAS Registry No. 87679-37-6] is the ethyl ester prodrug of trandolaprilat (2) [CAS Registry No. 87679-71-8], and it is a commonly prescribed cardiovascular drug for controlling and managing hypertension. It functions as an inhibitor of Angiotensin Converting Enzyme [ACE], which results in lowering blood pressure and is useful for treatment of heart failure. Trandolapril (1) can be used alone as oral drug. Alternatively, it can be used in combination with Verapamil, a calcium channel blocker, or with diuretics.

Pharmaceutical utility of trandolapril (1) for use as ACE inhibitor was first disclosed in U.S. Pat. No. 4,933,361. The general approach for preparing trandolapril (1) is based on the reaction of (2S,3aR,7aS)-benzyl octahydro-1H-indole-2-carboxylate hydrochloride (3) with (S)-2-((S)-1-ethoxy-1-oxo-4-phenylbutan-2-ylamino)propanoic acid (4) in the presence of a variety of coupling reagents to facilitate amide bond followed by hydrogenolysis of the benzyl ester. These coupling approaches to make trandolapril (1) are disclosed in U.S. Pat. No. 4,933,361 along with WO2004/101515, WO2005051909 WO2006/014916, WO2006/085332, EP 1724260, WO2007/003947 and US2009/0069574. Thus, it has been demonstrated that (2S,3aR,7aS)-benzyl octahydro-1H-indole-2-carboxylate hydrochloride salt (3) is a key component in this coupling reaction to manufacture trandolapril (1), and it is typically prepared from (2S,3aR,7aS)-octahydro-1H-indole-2-carboxylic acid (5) and benzyl alcohol.

Synthesis of (2S,3aR,7aS)-octahydro-1H-indole-2-carboxylic acid (5), which contains a trans-fused octahydroindole ring system, requires correct stereochemistry at the (2S)-carboxylic acid position to afford trandolapril (1). A number of methods have been disclosed for the synthesis of (5), which involve the use of animal source materials, such as pork liver, or hazardous chemical reagents, such as bromine and sodium cyanide, or optically active reagents for resolution of racemic mixtures (which can result in low yields), and are therefore not amenable for use in large scale preparation.
For instance, the synthesis described by Henning et al., Tetrahedron Lett. 1983, 24, 5339 is based on Favorski type ring contraction of halogenated trans-fused system, but gives a mixture of isomers. A different method described by Henning et al., in Tetrahedron Lett. 1983, 24, 5343 introduces trans-fused ring system efficiently but requires the use of hazardous reagent mercuric nitrate. Further, synthesis described by Brion et al. U.S. Pat. No. 4,879,392 and Tetrahedron Lett., 1992, 33, 4889 uses animal source reagent such pig liver esterase and require further chiral enrichment. WO 00/40555 and U.S. Pat. No. 6,559,318 rely on enzymatic resolution of 2-(2′,2′-methoxy ethyl)cyclohexylamine and require further chromatographic separation.
Other patents and patent applications such as U.S. Pat. No. 4,490,386, EP0088341 and US2009/0069574 describe a method, which uses α-1-phenylethyl amine for resolution of N-benzoyl (2S,3aR,7aS)-octahydro-1H-indole-2-carboxylic acid.
On the other hand, WO8601803, WO2004065368 and WO2006/014916 describe the preparation of (2S,3aR,7aS)-octahydro-1H-indole-2-carboxylic acid esters via resolution using 10-D-camphor sulfonic acid. In addition, WO2005/054194 and WO2006/085332 describes the preparation of (2S,3aR,7aS)-octahydro-1H-indole-2-carboxylic acid esters via resolution using (−)-dibenzoyl-L-tartrate. Finally, EP1724260 utilizes N-acetoxy-β-acyloxy alanine ester and its addition to an enamine followed by ring closure.
As described therein, these methods can be inefficient, expensive and do not result in high yield and/or high purity production of (2S,3aR,7aS)-octahydro-1H-indole-2-carboxylic acid (5). Therefore, in accordance with the present invention, there is a need for a process that is best suited for large scale preparation of (2S,3aR,7aS)-octahydro-1H-indole-2-carboxylic acid (5) that will reduce costs, decrease the number of manufacturing steps, decrease hazardous environmental waste, and increase efficiency of the manufacturing of (2S,3aR,7aS)-octahydro-1H-indole-2-carboxylic acid (5) and ultimately trandolapril.